Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell

总结 精氨酸加压素（AVP）和水通道（称为水通道蛋白（AQP））的调节异常可导致多种 临床上显著的水电解质问题，从严重脱水到低血浆钠。的 AVP在肾脏中的作用主要通过肾脏主要的AVP受体2（AVPR 2）介导。 cell. AVP敏感的水通道，AQP 2和AQP 3，促进水的重吸收，以防止脱水。 在这样做时，这些水通道的功能是浓缩尿液。基于我们令人信服的初步数据， 这项建议集中在第一个报道的AQP 3的修饰，赖氨酸282乙酰化，在调节 基质渗透性赖氨酸乙酰化对于基因表达也是重要的，并且其通过以下途径调节： 乙酰转移酶和脱乙酰酶（HDAC）。我们最近进行了一次系统性审查， 荟萃分析，并确定慢性HDAC抑制剂的使用，发生在治疗癌症，导致 在人类中经历液体-电解质紊乱的优势比显著>2。因此，确定函数 赖氨酸乙酰化在肾脏中的重要性从生理学角度和免疫学角度都是至关重要的。 了解HDAC抑制对水电解质平衡的临床影响。我们共同努力， 初步的数据使我们形成了一个总体假设，即肾脏AVPR 2/AQP的调节 赖氨酸乙酰化对调节尿浓缩能力和体液平衡至关重要。这将受到考验 目的1：验证AQP 3的赖氨酸乙酰化增加底物通量的假设 在促进尿液浓缩的主要细胞中。目的2：检验HDAC 1和HDAC 2 调节主细胞中AVPR 2/AQP轴的转录。我们将联合收割机无偏见的，系统生物学 用细胞到整个动物实验的方法来缩小我们对集中注意力的理解中的关键差距。 肾脏中的机制，并可能揭示新的治疗途径来治疗液体电解质紊乱。

SUMMARY Dysregulation of arginine vasopressin (AVP) and water channels, called aquaporins (AQPs), can lead to a variety of clinically-significant water-electrolyte problems, ranging from severe dehydration to low plasma sodium. The actions of AVP in the kidney are mediated via the AVP receptor 2 (AVPR2) predominantly on the kidney principal cell. The AVP-sensitive water channels, AQP2 and AQP3, promote water reabsorption to prevent dehydration. In doing so these water channels function to concentrate the urine. Based on our compelling preliminary data, this proposal focuses on the first reported modification of AQP3, lysine 282 acetylation, in the regulation of substrate permeability. Lysine acetylation is also important for gene expression and it is regulated via acetyltransferases and deacetylases (HDACs) enzymes. We recently performed a systemic review and metanalysis and determined that chronic HDAC inhibitor use, as occurs in the treatment of cancers, results in a significant >2 odds ratio of experiencing fluid-electrolyte disorders in humans. Thus, determining the functional significance of lysine acetylation in the kidney is critically important both from a physiological perspective and in understanding the clinical impact of HDAC inhibition on water-electrolyte balance. Together, our compelling preliminary data have led us to formulate the overarching hypothesis that regulation of the kidney AVPR2/AQP axis by lysine acetylation is critical in regulating urinary concentrating ability and fluid balance. This will be tested by the following two aims: Aim 1: To test the hypothesis that lysine acetylation of AQP3 increases substrate flux in the principal cell promoting urine concentration. Aim 2: To test the hypothesis that HDAC1 and HDAC2 regulate the transcription of the AVPR2/AQP axis in the principal cell. We will combine unbiased, system biology approaches with cell to whole animal experiments to close key gaps in our understanding of concentrating mechanisms in the kidney and may reveal new therapeutic avenues to treat fluid-electrolyte disorders.